It has been considered that hyperuricemia (increase in serum uric acid level) is deeply related to hypertension, renal disorders, and cardiovascular disorders. Because people with high uric acid levels have well known risk factors associated with cardiovascular disorders, it has been considered, based on such an epiphenomenon, that there is a relation between these risk factors and uric acid. In order to clarify the relation between risk factors associated with hypertension, renal disorders, and cardiovascular disorders and uric acid, immunological studies have been carried out by, for example, a multivariate analysis using other risk factors as controls.
The present inventors have developed rat models with mild hyperuricemia by administering a uricase inhibitor such as oxonic acid to rats. Interestingly, these hyperuricemic rat models develop hypertension, glomerular vascular disorders, and renal disorders (see Non-Patent Documents 1 to 6). It has been considered that the mechanism is not mediated by intrarenal crystal deposition, but instead involves activation of renin-angiotensin system and inhibition of nitric oxide synthase in macula densa (which is a group of cells that is densely packed in distal tubular epithelium, and strongly stained, and is in direct contact with juxtaglomerular cells) (see Non-Patent Documents 1 and 2). Further, the present inventors have reported that such vascular disorders occur independently of blood pressure (see Non-Patent Document 2).
Based on the finding that hyperuricemia induces vascular disorders independently of blood pressure, the effect of uric acid on vascular smooth muscle cells (VSMCs) has been examined. Rao et al. have reported that uric acid stimulated the expression of platelet-derived growth factor (PDGF) A-chain and rat VSMC cell proliferation (see Non-Patent Document 7). Further, the present inventors have shown that this pathway involves activation of expression of specific mitogen-activated protein kinase (MAP Kinase) (ERK), cyclooxygenase-2 (COX-2), PDGF A- and B-chains, and PDGF-α receptor mRNA (see Non-Patent Documents 2 to 4). Furthermore, the present inventors have shown that uric acid stimulates the expression of a monocyte chemotactic factor (MCP-1) in VSMCs, and that hyperuricemia stimulates vascular smooth muscle to promote cell proliferation and induce production of inflammatory cytokine (see Non-Patent Document 8).
However, a major question arises as to how uric acid enters VSMCs to induce these events. No receptor for uric acid has been known. Further, since uric acid is a water-soluble material, involvement of any transporter is absolutely necessary to allow uric acid to pass through cell membrane and enter smooth muscle cells.
Studies in renal cells have shown that urate transporters likely include both an organic anion transporter/exchanger (OAT family) and a voltage-sensitive channel (see Non-Patent Documents 9 to 11). Further, it has been shown that some members of OAT family, especially OAT1 and OAT3 (via basolateral membrane) and URAT1 (via luminal membrane) mediate urate uptake in renal cells (see Non-Patent Documents 12 to 15). Furthermore, a voltage-sensitive channel/transporter mechanism has been shown, and a putative transporter (UAT) has been identified (see Non-Patent Documents 16 to 18). However, no study has been made to determine which channels/transporters are expressed in rat VSMCs and whether they function or not. Further, it has not been known that what kind of material functions as a urate transporter in VSMCs.
The present inventors have identified a novel clone (URAT1) by a 3′-RACE method using human kidney cell mRNA. This urate transporter URT1 (urate transporter 1) has the ability to transport uric acid and its analogs from one side to the other side via cell membrane, and is an exchange transporter (urate/anion exchanger) that allows the anion at the other side of cell membrane to be an exchange substrate (see Patent Document 1).
The following prior art documents related to the present invention are incorporated herein by reference.    Patent Document 1: Japanese Patent Application Laid-open No. 2003-93067    Non-Patent Document 1: Mazzali M, Hughes J, et al., Hypertension, 2001; 38, 1101-1106    Non-Patent Document 2: Mazzali M, Kanellis J, et al., Am. J. Physiol. Renal Physiol., 2002; 282, F991-997    Non-Patent Document 3: Watanabe S, Kang D H, et al., Hypertension, 2002; 40, 355-360    Non-Patent Document 4: Kang D H, Nakagawa T, et al., J. Am. Soc. Nephrol., 2002; 13, 2888-2897    Non-Patent Document 5: Nakagawa T, Mazzali M, et al., Am. J. Nephrol., 2003; 23, 2-7    Non-Patent Document 6: Sanchez-Lozada L G, Tapia E, et al., Am. J. Physiol. Renal Physiol., 2002; 283, F1105-F1110    Non-Patent Document 7: Rao G N, Corson M A, et al., J. Biol. Chem., 1991; 266, 8604-8608    Non-Patent Document 8: Kanellis J, Watanabe S, et al., Hypertension, 2003; 41, 1287-1293    Non-Patent Document 9: Roch-Ramel F, Guisan B, et al., J. Pharm. Exp. Ther., 1997; 280, 839-845    Non-Patent Document 10: Roch-Ramel F, Werner D, et al., Am. J. Physiol. Renal Physiol., 1994; 266, F797-F805    Non-Patent Document 11: Knorr B A, Beck J C, et al., Kidney Int., 1994; 45, 727-736    Non-Patent Document 12: Sekine T, Cha S H, et al., Eur. J. Physiol., 2000; 440, 337-350    Non-Patent Document 13: Cha S H, Sekine T, et al., Mol. Pharmacol., 2001; 59, 1277-1286    Non-Patent Document 14: Kimura H, Chairoungdua A, et al., Nature, 2002; 417, 447-452    Non-Patent Document 15: Motohashi H, Sakurai Y, et al., J. Am. Soc. Nephrol., 2002; 13, 866-874    Non-Patent Document 16: Leal-Pinto E, Cohen B E, et al., J. Membrane. Biol., 1999; 169, 13-27    Non-Patent Document 17: Leal-Pinto E, Tao W, et al., J. Biol. Chem., 1997; 272, 617-625    Non-Patent Document 18: Lipkowitz M S, Leal-Pinto E, et al., J. Clin. Invest., 2001; 107, 1103-1115